Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Using a genetic screen, we have shown that small nucleolar RNAs (snoRNAs) embedded within introns of the ribosomal protein L13a (rpL13a) gene act in mammalian cells through non-canonical mechanisms to serve as critical mediators in the propagation of oxidative stress and cell death in response to lipotoxicity. This study will extend our findings by elucidating the mechanism of action of rpL13a snoRNAs, by characterizing genes that relate to their biogenesis and downstream actions, and by examining their contributions to the pathogenesis of cardiac lipotoxicity in a mouse model. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in cardiovascular complications of metabolic diseases.